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Blood, 1 July 2007, Vol. 110, No. 1, pp. 142-150.
Prepublished online as a Blood First Edition Paper on March 15, 2007; DOI 10.1182/blood-2006-02-002931.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
CD13/APN regulates endothelial invasion and filopodia formation
Nenad Petrovic1,2,
Wolfgang Schacke1,
J. Reed Gahagan1,
Catherine A. O'Conor1,
Beata Winnicka1,
Rebecca E. Conway1,
Paola Mina-Osorio1, and
Linda H. Shapiro1
1 Department of Cell Biology, Center for Vascular Biology, University of Connecticut Health Center, Farmington;
2 Faculty of Pharmacy, University of Sydney, NSW, Australia
CD13/aminopeptidase N is a transmembrane peptidase that is induced in the vasculature of solid tumors and is a potent angiogenic regulator. Here, we demonstrate that CD13 controls endothelial cell invasion in response to the serum peptide bradykinin by facilitating signal transduction at the level of the plasma membrane. Inhibition of CD13 abrogates bradykinin B2 receptor internalization, leading to the attenuation of downstream events such as bradykinin-induced activation of Cdc42 and filopodia formation, and thus affects endothelial cell motility. Investigation into mechanisms underlying this block led us to focus on B2R internalization via membrane-dependent mechanisms. Membrane disruption by depletion of cholesterol or trypsinization halts B2R internalization, invasion, and filopodia formation, which can be recovered with addition of cholesterol. However, this functional recovery is severely impaired in the presence of CD13 antagonists, and the distribution of membrane proteins is disordered in treated cells, suggesting a role for CD13 in plasma membrane protein organization. Finally, exogenous expression of wild-type but not mutant CD13 further alters protein distribution, suggesting peptidase activity is required for CD13's regulatory activity. Therefore, CD13 functions as a novel modulator of signal transduction and cell motility via its influence on specific plasma membrane organization, thus regulating angiogenesis.
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